1,4-thiazine derivative, and cardiotonic agent comprising it as effective component

ABSTRACT

A novel 1,4-thiazine derivative represented by the formula I, a pharmaceutically acceptable acid addition salt thereof, a process for preparation thereof and a cardiotonic agent comprising it as an effective component; ##STR1## wherein R 1  and R 2  represent respectively hydrogen atom, lower alkyl group, lower alkoxy group, amino group, lower alkyl-amino group, aryl-amino group, hydroxy group, aryl group or 5- or 6-membered heterocyclic residue; 
     R 3  and R 4  represent hydrogen atom or lower alkyl group; and 
     R 5  represents N-containing heterocyclic residue and is not pyridinyl group when R 1  and R 2  represent hydrogen atom and R 3  and R 4  represent hydrogen atom or lower alkyl group.

TECHNICAL FIELD

The present invention relates to a novel 1,4-thiazine derivativerepresented by the formula I, a pharmaceutically acceptable acidaddition salt thereof, a process for preparation thereof and acardiotonic agent comprising it as an effective component; ##STR2##wherein R₁ and R₂ represent respectively hydrogen atom, lower alkylgroup, lower alkoxy group, amino group, lower alkyl-amino group,aryl-amino group, hydroxy group, aryl group or 5- or 6-memberedheterocyclic residue;

R₃ and R₄ represent hydrogen atom or lower alkyl group; and

R₅ represent N-containing heterocyclic residue and is not pyridinylgroup when R₁ and R₂ represent hydrogen atom and R₃ and R₄ representhydrogen atom or lower alkyl group.

BACKGROUND ART

Known process for synthesis of 1,4-thiazine derivative are for example aprocess starting with a thioglycol amide derivative as disclosed inJournal of the American Chemical Society, 70, 3517 (1948), a processstarting with a tricyclic compound as disclosed in Japanese PatentPublication No. 16630/1967 and a process starting with a thiazoliumcompound as disclosed in Japanese Patent Publication No. 29182/1970.

The fact that pyridone derivatives and pyridazinone derivatives possessproperties affecting the cardiovascular systems is described in forexample Japanese Patent Provisional Publication No. 48675/1977, Journalof Medicinal Chemistry, 17, 273 (1974) and Japanese Patent ProvisionalPublication No. 109771/1982.

However, 1,4-thiazine derivatives having nitrogen-containingheterocyclic residue at position 6 are novel compounds and no techniqueis known for synthesis of such compounds. Furthermore, there is noreport on cardiotonic activity of such compounds.

DISCLOSURE OF THE INVENTION

We, the inventors succeeded in synthesis of novel 1,4-thiazinederivatives as disclosed in prior Japanese Patent Application No.170862/1983. As a result of our further intensive researches, we foundthat novel 1,4-thiazine derivatives having nitrogen-containingheterocyclic residue at position 6 have cardiotonic activity andcompleted the present invention. The present invention is directed to anovel 1,4-thiazine derivative having a nitrogen-containing heterocyclicresidue at position 6, a pharmaceutically acceptable acid addition saltthereof, a process for preparation thereof and a cardiotonic agentcomprising it as an effective component.

Terms used for definition of letters in the above formula I by which thecompound of the present invention is represented are defined andexemplified in the following.

The term "lower" refers to group having 1 to 6 carbon atoms unlessotherwise indicated.

The "lower alkyl group" may be alkyl group which are arranged asstraight or branched chains and may be methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, n-hexyl or thelike.

The "lower alkoxy group" may be methoxy, ethoxy, n-propoxy, iso-propoxy,n-butoxy, iso-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy or the like.

The "aryl group" may be phenyl, tolyl, xylyl, mesityl, cumenyl, biphenylor the like which may unsubstituted or may be substituted with loweralkyl group, lower alkoxy group, halogen atom, aldehyde group, acylgroup, cyano group, nitro group, hydroxy group or the like.

The term "lower alkyl-amino group" means amino groups substituted withabove-mentioned lower alkyl groups. The "lower alkyl-amino group" may bemethylamino, dimethylamino, ethylamino, diethylamino, n-hexylamino orthe like.

The term "arylamino group" means amino groups substituted withabove-mentioned aryl group. The "arylamino" group may be anilino,toluidino, xylidino or the like.

The term "5- or 6-membered heterocyclic residue" means oxygen-, sulfur-,or nitrogen-containing 5- or 6-membered heterocyclic residue. The "5- or6-membered heterocyclic residue" may be furyl, thienyl, pyrrolyl,pyrano, pyridinyl, pyridazino, pyrimidino, piperidino, piperazino ormorpholino or the like.

The term "N-containing heterocyclic residue" means nitrogen-containing5- or 6-membered mono or condensed heterocyclic residue which may beunsubstituted or may be substituted by lower alkyl group, lower alkoxygroup, halogen atom, cyano group, nitro group, aldehyde group, acylgroup, hydroxy group, lower alkoxycarbonyl group or the like. The"N-containing heterocyclic residue" may be pyridinyl, pyridazinyl,pyrimidinyl, pyrazinyl, quinolinyl, iso-quinolinyl, cinnolinyl,quinazolinyl, quinoxalinyl, phthalazinyl, acridinyl, methylpyridinyl,methoxypyridinyl, chloropyridinyl, formylpyridinyl, cyanopyridinyl,nitropyridinyl, acetylpyridinyl, hydroxypyridinyl, methoxyquinolinyl,methylpyridazinyl, methoxycarbonylpyridinyl, thiazolyl, piperidinyl,piperadinyl, morpholinyl or the like.

It is to be noted that some of the compounds according to the presentinvention may be alternatively represented by its tautomers. Forexample, a compound of the formula I having hydroxy group adjacent tonitrogen atom of pyridine ring may exist in the following two forms.##STR3##

Accordingly all of such isomers are included within the category of thecompound of the formula I.

The compounds according to the present invention are for example asfollows:

5-methyl-6-(4-quinolinyl)-2H-1,4-thiazin-3(4H)-one;

5-methyl-6-(4-pyridazinyl)-2H-1,4-thiazin-3(4H)-one;

5-methyl-6-(3-chloro-4-pyridinyl)-2H-1,4-thiazin-3(4H)-one;

5-methyl-6-(3-formyl-4-pyridinyl)-2H-1,4-thiazin-3(4H)-one;

5-methyl-6-(3-cyano-4-pyridinyl)-2H-1,4-thiazin-3(4H)-one;

5-methyl-6-(3-methoxycarbonyl-4-pyridinyl)-2H-1,4-thiazin-3(4H)-one;

5-methyl-6-(3-acetyl-4-pyridinyl)-2H-1,4-thiazin-3(4H)-one;

5-methyl-6-(6-methoxy-4-quinolinyl)-2H-1,4-thiazin-3(4H)-one;

5-methyl-6-(3-methyl-4-pyridazinyl)-2H-1,4-thiazin-3(4H)-one;

5-methyl-6-(3-methyl-4-pyridinyl)-2H-1,4-thiazin-3(4H)-one;

5-methyl-6-(2-thiazolyl)-2H-1,4-thiazin-3(4H)-one;

2,5-dimethyl-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-one;

2-ethyl-5-methyl-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-one;

2-methoxy-5-methyl-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-one;

2,2-dimethoxy-5-methyl-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-one;

2-amino-5-methyl-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-one;

2-diethylamino-5-methyl-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-one;

2-hydroxy-5-methyl-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-one;

2-(4-hydroxyphenyl)-5-methyl-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-one;

5-methyl-2-phenylamino-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-one;

2-(2-furyl)-5-methyl-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-one;

5-methyl-2-(2-thienyl)-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-one;

5-methyl-2-(2-pyrrolyl)-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-one;

2,5-dimethyl-6-(4-pyridazinyl)-2H-1,4-thiazin-3(4H)-one;

2,5-dimethyl-6-(4-quinolinyl)-2H-1,4-thiazin-3(4H)-one;

2,5-dimethyl-6-(3-methoxy-4-pyridinyl)-2H-1,4-thiazin-3(4H)-one;

2,5-dimethyl-6-(6-methoxy-4-quinolinyl)-2H-1,4-thiazin-3(4H)-one;

2,5-dimethyl-6-(3-acetyl-4-pyridazinyl)-2H-1,4-thiazin-3(4H)-one;

5-methyl-2-piperidino-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-one;

5-methyl-2-morpholino-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-one;

or the like.

The compound of the formula I according to the present invention isprepared for example according to the following alternative methods.

First method:

When a 1,4-thiazine derivative of the formula III (in which R₁, R₂, R₃,and R₄ are as defined above) is reacted with a known compound of theformula A--X' (in which A represents a residue ##STR4## in which Xrepresents a halogen atom and n is an integer of 1 to 3 and X'represents a halogen atom which may be the same as or different from X)and a known compound of the formula R₅ --H (in which R₅ is as definedabove), a novel 1,4-thiazine derivative of the formula II is obtained.##STR5## wherein R₁, R₂, R₃, R₄ and A are as defined above and R₅ 'represents dihydro form residue of N-containing heterocyclic group.

This reaction is completed by merely mixing equal mole concentration ofthe compound of the formula III and the compound of the formula A--X'and more than equal mole concentration of the compound of the formula R₅--H under atmospheric pressure at ambient temperature, and stirring themixture in the presence of a solvent for more than 30 minutes preferablyfrom 1 to 7 hours.

The solvent used in this reaction may be nitrile such as acetonitrile,ether such as tetrahydrofran, halogenated hydrocarbon such asdichloromethan or the like. Alternatively, the compound havingN-containing heterocyclic residue itself may also be used as thesolvent.

The compound having N-containing heterocyclic residue may be pyridine,pyridazine, pyrimidine, pyrazine, quinoline, isoquinoline, cinnoline,quinazoline, quinoxaline, phthalazine, acridine, phenazine, thiazole,piperidine, piperazine, morpholine or the like, or derivative thereofhaving substituent such as lower alkyl group, lower alkoxy group,halogen atom, cyano group, nitro group, aldehyde group, acyl group,hydroxy group or the like. Such derivative may be 3-methoxypyridine,3-chloropyridine, pyridine-3-aldehyde, 3-methylpyridine,nicotinonitrile, 3-acetylpyridine, methyl nicotinate, 3-nitropyridine,3-hydroxypyridine, 6-methoxyquinoline, 3-methylpyridazine or the like.

Then, the residue A of the above-mentioned compound of the formula A--X'connected to position 6 of the compound of the formula II, that ishalogenated ethoxycarbonyl group is removed to thereby obtain a compoundof the formula I.

This may be effected in various ways; a typical way is as follows.

The compound of the formula II is reacted with sulfur at elevatedtemperature to remove the residue. More specifically, the compound ofthe formula II is stirred with 5 fold amount of finely ground sulfur andthe mixture is heated under atmospheric pressure at 120° to 200° C. for0.5 to 8 hours, preferably at 140° C. to 180° C. for 1 to 5 hours toobtain a compound of the formula I. Generally, no solvent is needed inthis reaction; however, N,N-dimethylformamide, dimethyl sulfoxide, etc.may be employed. In the case of using such solvent, the amount of sulfurmay be substantially half as much as that of the compound of the formulaII. ##STR6## wherein R₁, R₂, R₃, R₄, R₅, A and R₅ ' are as definedabove.

Alternatively, the compound of the formula II may be reacted with zincat elevated temperature for such removal. In this case, the substituentat position 6 is still a dihydro residue so that oxidation is needed forobtaining an intended compound of the formula I. More specifically, thecompound of the formula II is reacted with excessive amount of zincunder atmospheric pressure at 30° to 80° C. for 1 to 4 hours, preferably50° to 60° C. for 2 to 3 hours in the presence of a solvent. Then, anoxidizing agent such as 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) isadded thereto and the mixture is stirred at 30° to 80° C. for 1 to 4hours, preferably 50° to 60° C. for 2 to 3 hours to obtain a compound ofthe formula I. A solvent used in this reaction may be nitrile such asacetonitrile, ether such as tetrahydrofuran, sulfoxide such asdimethylsulfoxide, amide such as dimethylformamide or the like. ##STR7##wherein R₁, R₂, R₃, R₄, R₅, A and R₅ ' are as defined above.

Purification of the compounds of the formula I and II may beaccomplished by recrystallization from lower alcohol such as methanol,ethanol or isopropanol, ketone such as acetone, halogenated hydrocarbonsuch as chlorofrom, carboxylic acid ester such as ethyl acetate,aromatic hydrocarbon such as benzene, ether such as diethylether ornitrile such as acetonitrile or the like.

Alternatively, such purification may also be accomplished by columnchromatography, flash column chromatography or thin layer chromatographyusing silica gel. Preferably used in column chromatography is silica gelhaving particle size of 100-200 mesh such as Wakogel C-200 (manufacturedby Wako Pure Chemical Industries, Ltd., in Japan); in the case of flashcolumn chromatography, silica gel having particle's porous diameter of40-63μ such as silica gel 60 (Art 9385) (manufactured by Merck & Co.Inc. in USA); and in the case of thin layer chromatography, silica gelhaving particle's average porous diameter of 6 nm which fluoresces inthe region of 254 nm such as Merck TCL plate silica gel 60F₂₅₄(manufactured by Merck & Co. Inc. in USA).

The compound of the formula II may be directly used in the subsequentstep, without purification.

The starting material 1,4-thiazine derivative of the formula III may beprepared in the following ways.

The starting material of the formula III wherein R₃ is a hydrogen atommay be prepared according to the ways proposed by H. Sokol et al. in J.Am. Chem. Soc., 70, 3517 (1948), C. R. Johnson et al. in J. Hetero.Chem., 6, 247-249 (1969) and G. V. Rao et al. in Synthesis, 136 (1972).

The starting material of the formula III wherein R₃ is lower alkyl groupmay be prepared according to the ways proposed by G. D. Stevens et al.in J. Am. Chem. Soc. 80, 5198 (1958) and M. Hojo et al. in Synthesis,272 (1979).

In view of the state of the reaction system (the reactivity and degreeof dissociation) and the easy availability, an especially preferredcompound of the formula A--X' is one in which X and X' representchlorine atom and n is 3, i.e. 2,2,2-trichloroethylchloroformate.

Second method:

1,4-Thiazine derivative having substituent at position 2 may be obtainedby following steps.

1,4-Thiazine derivative with no substituent at position 2, i.e. thecompound of the formula I"', is prepared according to the first methoddescribed above. ##STR8## wherein R₃, R₄, R₅, A and R₅ ' are as definedabove.

Then the substituent is introduced to position 2 of the compound of theformula I"' according to the way proposed by M. Hojo et al. inSynthesis, 312, 424 (1982) or the like. More specifically, the compoundof the formula I"' is reacted with a peracid of the formula A'--COOOH(in which A' represents lower alkyl group, alicyclic compound residue oraryl group) to obtain a novel, 1,4-thiazine derivative represented bythe compound of the formula IV. ##STR9## ps wherein R₃, R₄, R₅ and A'are as defined above.

This reaction is completed by merely mixing substantially equal moleconcentration of the compound of the formula I"' and the compound of theformula A'--COOOH under atmospheric pressure and ice-cooling andstirring the mixture in the presence of solvent for a few minutes.

The solvent, which is used in this reaction, may be halogenatedhydrocarbon such as dichloromethane, nitrile such as acetonitrile, ethersuch as tetrahydrofran, sulfoxide such as dimethylsulfoxide or amidesuch as dimethylformamide or the like.

As for the peracid, aliphatic peroxycarboxylic acid such as performicacid or peracetic acid, alicyclic peroxycarboxylic acid such ascyclohexaneperoxycarboxylic acid, aromatic peroxycarboxylic acid such asperbenzoic acid or monoperoxyphthalic acid, or derivative thereof may beemployed. In view of the state of the reaction system (the reactivityand degree of dissociation) and the easy availability,m-chloroperbenzoic acid is especially preferred.

Then, the compound of the formula IV is reacted with a nucleophilicreagent of the formula R₁ '--H (in which R₁ ' is lower alkoxy group,amino group, lower alkyl-amino group, aryl-amino group, hydroxy group,aryl group or 5- or 6-membered heterocyclic residue) to obtain anintended compound of the formula I". ##STR10## wherein R₁ ', R₃, R₄, R₅and A' are as defined above.

This reaction is completed by merely mixing substantially equal moleconcentration of the compound of the formula IV and compound of theformula R₁ '--H under atmospheric pressure at ambient temperature andstirring the mixture in the presence of a solvent.

Alternatively, for accelaration of the reaction the reaction may becarried out at the elevated temperature of 50°-70° C.

In this reaction, amide such as dimethylformamide, nitrile such asacetonitrile, ether such as tetrahydrofran, sulfoxide such asdimethylsulfoxide or halogenated hydrocarbon such as dichloromethane orthe like may be used as a solvent. Alternatively, the compound of theformula R₁ '--H itself may be used as a solvent.

As for the nucleophilic reagent of the formula R₁ '--H, lower alcoholsuch as methanol, ethanol or iso-propanol, ammonium salt such asammonium carbonate, amine such as methylamine or diethylamine,aryl-amine such as aniline, aromatic compound such as phenol,heterocyclic compound such as furan, piperazine, morphorine, thiophene,pyrrole, imidazole or water or the like may be employed.

Introduction of a substituent except for hydrogen atom at position 2 maybe similarly carried out such that the compound of the formula I" isreacted with a nucleophilic reagent of the formula R₂ '--H (in which R₂' represents lower alkoxy group, amino group, lower alkyl-amino group,aryl-amino group, hydroxy group, aryl group or 5- or 6-memberedheterocyclic residue).

As for the nucleophilic reagent of the formula R₂ '--H, lower alcoholsuch as methanol or ethanol, ammonium salt such as ammonium carbonate,amine such as methylamine or diethylamine, aryl-amine such as aniline,aromatic compound such as phenol, heterocyclic compound such as furan,piperazine, morphorine, thiophene, pyrrole or imidazole, water or thelike may be employed. ##STR11## wherein R₁ ', R₃, R₄, R₅, A' and R₂ 'are as defined above.

This reaction is completed by mixing the compound of the formula I",with the compound of the formula A'--COOOH under atmospheric pressureand ice-cooling and stirring the mixture in the presence of a solventfor reaction, and adding a compound of the formula R₂ '--H to thereaction mixture under atmospheric pressure at ambient temperature, andstirring the mixture in the presence of a solvent for reaction. Foracceleration of the reaction the reaction may be carried out at theelevated temperature of 50°-70° C. The compound of the formula I' inwhich substituents R₁ ' and R₂ ' at position 2 are the same may beobtained by reacting one mole concentration of the compound of theformula I" with more than two mole concentration of the compound of theformula A'--COOOH and compound of the formula R₁ '--H.

The first method is preferable to use when the substituents R₁ and R₂ atposition 2 of the compound of the formula I are hydrogen atom, loweralkyl group or lower alkoxy group, In the other cases, the second methodis preferable to use.

The compound of the formula I may be converted into a pharmaceuticallyacceptable salt by using an appropriate acid.

Such appropriate acid is, for example, inorganic acid such ashydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid, ororganic acid such as acetic, propionic, glycolic, lactic, pyruvic,malonic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic,cinnomic, manderic, methanesulfonic, hydroxyethanesulfonic,benzenesulfonic, p-toluenesulfonic, cyclohexanesulfamic, salicyclic,p-aminosalicylic, 2-phenoxybenzoic or 2-acetoxybenzoic acid.

The pharmacological effects of the compound of the formula I will now bedescribed; ##STR12## wherein R₁, R₂, R₃, R₄ and R₅ are as defined above.

Apparatuses used in the following pharmacological tests are

Magnus' bath: supplied by Kabushiki Kaisha Natsume Seisakusho

Pen-writing oscillograph: supplied by Nippon Koden Kabushiki Kaisha

Force displacement pickup: supplied by Nippon Koden Kabushiki Kaisha

Strain pressure amplifier: supplied by Nippon Koden Kabushiki Kaisha

Electrically simulating device: supplied by Nippon Koden Kabushki Kaisha

Pharmacological Test 1

Effect on isolated left atrium of guinea pig was tested according to themethod described in Basic Lectures of Medicine Development, Volume V,Pharmacological Test Methods, Part 2, page 534 (1971) published byChizin Shokan Kabushiki Kaisha in Japan. A 7-weeks-old male Hartleyguinea pig (having body weight of about 350 g) was stunned by a blow onthe head. The heart was cut out, and the left atrium was taken out inKrebs-Henseleit solution (prepared by adding distilled water forinjection to 6.92 g of sodium chloride, 0.35 g of potassium chloride,0.28 g of calcium chloride, 0.29 g of magnesium sulfate, 0.16 g ofmono-basic potassium phosphate, 2.1 g of sodium bicarbonate and 1.8 g ofglucose so that the total amount was 1000 ml) which was sufficientlybubbled with oxygen gas. The isolated left atrium was suspended inMagnus' bath at 30° to 32° C. and isometric contraction was recorded bythe pen-writing oscillograph through the strain pressure amplifierconnected to the force displacement pickup.

The atrium was stimulated electrically at 0.5 cps for 5 msec under avoltage of 20% above threshold. The nutritive liquid was Krebs-Henseleitsolution through which 95% oxygen gas and 5% carbon dioxide was blown.Effect of each sample was tested 60 to 90 minutes after stimulation atwhich the generated tension became stable. The results are shown inTable 1. In this test, corresponding concentration of each sample was1×10⁻⁴ mole.

                                      TABLE 1                                     __________________________________________________________________________    Effect on Isolated Left Atrium of Guinea Pig                                  Compound of the formula I of the Invention                                                                  Tension increment                               R.sub.1   R.sub.2                                                                           R.sub.3                                                                           R.sub.4                                                                           R.sub.5 (mg)                                            __________________________________________________________________________    H         H   H   CH.sub.3                                                                           ##STR13##                                                                            300 ± 125                                    H         H   H   CH.sub.3                                                                           ##STR14##                                                                            225 ± 123                                    H         H   H   CH.sub.3                                                                           ##STR15##                                                                            426 ± 56                                     H         H   H   CH.sub.3                                                                           ##STR16##                                                                            278 ± 56                                     H         H   H   CH.sub.3                                                                           ##STR17##                                                                            214 ± 56                                     CH.sub.3  H   H   CH.sub.3                                                                           ##STR18##                                                                            780 ± 93                                     C.sub.2 H.sub.5                                                                         H   H   CH.sub.3                                                                           ##STR19##                                                                            925 ± 32                                      ##STR20##                                                                              H   H   CH.sub.3                                                                           ##STR21##                                                                            230 ± 92                                     NHCH.sub.3                                                                              H   H   CH.sub.3                                                                           ##STR22##                                                                            233 ± 46                                      ##STR23##                                                                              H   H   CH.sub.3                                                                           ##STR24##                                                                            207 ± 47                                     __________________________________________________________________________

It was confirmed that administration of the compound according to thepresent invention will drastically increase the contractile force ofcardiac muscle.

Pharmacological Test 2

Effect on isolated auricule was tested according to the method of L. J.Mcleod described in Pharmacological Experiments on Intact Preparations,pages 112-115 (1970). A 7-weeks-old male Hartley guinea pig (having bodyweight of about 350 g) was killed by a blow on the head. The heart wascut out, and all the tissues except for the auricule were cut away inRinger-Locke solution (prepared by adding distilled water for injectionto 9.0 g of sodium chloride, 0.25 g of potassium chloride, 0.15 g ofcalcium chloride and 1.0 g of glucose so that the total amount was 1000ml). One of cotton threads, which were tied to each tip of the auricule,is attached to Magnus' bath and the other to the force displacementpickup. The Magnus' bath was maintained at 30°±1° C. through whichoxygen gas was bubbled. When the rhythmic movement and contraction ofcardiac muscle became constant, recording by the pen-writingoscillograph was started. After 1 minute, sample compound was injectedand recording was conducted for 5 minutes. After completion ofrecording, the isolated auricule was washed with Ringer-Locke solutionuntil the rhythmic movement and contraction of cardiac muscle becameconstant. After 30 minutes, recording by the pen-writing oscillographwas started again. The obtained results are shown in Table 2. In thistest, corresponding concentration of each sample was 3×10⁻⁴ mole.

                  TABLE 2                                                         ______________________________________                                        Effect on Isolated Auricule                                                                          Tension  Increase                                      Compound of the formula I of the Invention                                                           increment                                                                              in heart                                      R.sub.1                                                                              R.sub.2 R.sub.3                                                                        R.sub.4 R.sub.5  (mg)   rate (%)                              ______________________________________                                        H      HH       CH.sub.3                                                                               ##STR25##                                                                             190    2.2                                   H      HH       CH.sub.3                                                                               ##STR26##                                                                             250    9.4                                   CH.sub.3                                                                             HH       CH.sub.3                                                                               ##STR27##                                                                             158    2.0                                   C.sub.2 H.sub.5                                                                      HH       CH.sub.3                                                                               ##STR28##                                                                             226    2.4                                   ______________________________________                                    

It was confirmed that administration of the compound of the presentinvention will significantly increase the contractile force of cardiacmuscle with little increase of heart rate.

Pharmacological Test 3

The acute toxicity was determined according to the Litchfield-Wilcoxonmethod, J. Pharm. Exp. Ther., 96, 99 (1947) using 6-weeks-old male ddYmice (having body weight of 19-24 g) while administrating the samplecompound in intraperitonial injection. The results are shown in Table 3.

                  TABLE 3                                                         ______________________________________                                        Acute toxicity                                                                Compound of the formula I of the Invention                                                                LD.sub.50                                         R.sub.1                                                                              R.sub.2 R.sub.3 R.sub.4                                                                              R.sub.5   (mg/Kg)                               ______________________________________                                        H      H       H       CH.sub.3                                                                              ##STR29##                                                                              270                                   H      H       H       CH.sub.3                                                                              ##STR30##                                                                              275                                   CH.sub.3                                                                             H       H       CH.sub.3                                                                              ##STR31##                                                                              230                                   C.sub.2 H.sub.5                                                                      H       H       CH.sub.3                                                                              ##STR32##                                                                              130                                   ______________________________________                                    

From the results of the above pharmacological test 1 to 3 the compoundof the present invention was found to cause significant increase ofcontractile force in cardiac muscle with little increase of heart rateand to have low acute toxicity so that the compound of the presentinvention is effective in curing and preventing heart diseases.

The compound of the present invention may be administrated to human bodyorally, by injection (intravenously, subcutaneously or intramuscularly)or in any other manner.

When the compound of the present invention is in the form of solidpreparations for oral administration, the preparations may be tablets,granules, powders, capsules or the like. The preparations may containadditives, for example, an excipient such as a saccharide or cellulosepreparation, a binder such as starch paste or methyl cellulose, afiller, a disintegrator and so on, all being ones usually used inmanufacture of medical preparations. In the case where the compound ofthe present invention is employed as oral liquid preparations, they maybe of any form selected from aqueous preparations for internal use,suspensions, emulsions, syrups, etc.; alternatively they may be in theform of dried products which are dissolved prior to the use.

The compound of the present invention may be injected in the form ofaqueous solutions, suspensions or oily or aqueous emulsions, but usuallythe injections are prepared by dissolving or suspending them in aqueousliquid media such as sterile water or physiological saline solutions. Ifnecessary, conventionally used dissolving agents, stabilizers,preservatives, additives for preparing isotonic solutions, etc. may beadded to the injections.

BEST MODE FOR CARRING OUT THE INVENTION

The invention will be understood more readily with reference to thefollowing examples; however these examples are intended to illustratethe invention and are not to be constituted to limit the scope of theinvention. In the examples, the mesurements were carried out by usingthe following apparatuses.

Melting point: Model MP-1 supplied by Yamato Kagaku Kabushiki Kaisha

Mass analysis (MS): Model M-60 supplied by Kabushiki Kaisha HitachiSeisakusho

Infrared absorption spectrum (IR): Model 260-10 supplied by KabushikiKaisha Hitachi Seisakusho

Nuclear magnetic resonance (NMR): Model FX-270 supplied by Nippon DenshiKabushiki Kaisha

Elementary analysis: Model MT-2 supplied by Kabushiki Kaisha YanagimotoSeisakusho

EXAMPLE 1 Preparation of5-methyl-6-(4-quinolinyl)-2H-1,4-thiazin-3(4H)-one

2,2,2-Trichloroethylchloroformate (4.8 ml) was added dropwise to asuspension of 5-methyl-2H-1,4-thiazin-3(4H)-one (4 g) in dry quinoline(25 ml) under cooling at 0° to 5° C. and the mixture was stirred atambient temperature for 3 hours. The solvent was removed under reducedpressure and the residue was extracted with chloroform, was washed with2N hydrochloric acid and successively with water, was dried overmagnesium sulfate. The solvent was removed to give dark red oily product(4 g). The oily product (4 g) and sulfur sublimed (20 g) were mixed andstirred at 140°-145° C. for 4 hours and then the mixture was cooled toambient temperature. The remaining solid was extracted with methanol andthe extract was concentrated. The residue was dissolved in 50 ml of 2Nhydrochloric acid. The insoluble solid was removed by filtration and thefiltrate was adjusted to pH about 7.5 by 2N aqueous sodium hydroxideunder cooling and allow to cool overnight. The resulting precipitateswere collected by filtration and were chromatographed on silica gel(Wakogel C-200 with 100-200 mesh, manufactured by Wako Pure ChemicalIndustries, Ltd.) column, using chloroform-methanol (=40:1) as aneluant. The residue was recrystallized from methanol with use ofcharcoal to give the titled compound (0.66 g, yield 8.4%) as pale orangecrystals.

Melting point: 174.5°-175.5° C.

IR spectrum ν_(max) ^(KBr) (cm⁻¹): 3200, 3100, 1680, 1640

MS spectrum: M⁺ 256

NMR spectrum (CDCl₃, TMS, δ): 1.77 (3H, s), 3.56 (2H, s), 7.35 (1H, d),7.60 (1H, t), 7.75 (1H, t), 7.95 (2H, d+s), 8.15 (1H, d) 8.95 (1H, d)

The dark red oily product to be reacted with sulfur sublimed waschromatographed on silica gel (Wakogel C-200) column, using ethylacetate-n-hexane (=1:1) as an eluant to give5-methyl-6-[1-(2,2,2-trichloroethoxycarbonyl)-1,4-dihydro-4-quinolinyl]-2H-1,4-thiazin-3(4H)-oneas pale yellow crystals.

Melting point: 166°-167° C.

IR spectrum ν_(max) ^(KBr) (cm⁻¹): 3200, 3060, 1710, 1660, 1630

MS spectrum: M⁺ 432

NMR spectrum (CDCl₃, TMS, δ): 2.13 (3H, s), 3.12 (2H, ABq), 4.62 (1H,d), 4.93 (2H, s), 5.20 (1H, dd), 7.10-7.30 (4H, m), 7.90 (1H, s), 8.10(1H, d)

Example 2 (i) Preparation of intermediate:5-methyl-6-[1-(2,2,2-trichloroethoxycarbonyl)-1,4-dihydro-4-pyridazinyl]-2H-1,4-thiazin-3(4H)-one

2,2,2-Trichloroethylchloroformate (3.44 ml) was added dropwise to asolution of pyridazine (1.44 ml) in dry acetonitrile (40 ml) underice-cooling, and the mixture was stirred for 10 minutes.5-Methyl-2H-1,4-thiazin-3(4H)-one (1.29 g) was added to the mixture. Thereaction mixture was further stirred at ambient temperature for 1 hour.Then, the solvent was removed under reduced pressure and the residue wasextracted with chloroform. The extract was washed with 2N hydrochloricacid and successively with water, was dried over mangnesium sulfate andthe solvent was removed. The residue was chromatographed on silica gel(Wakogel C-200) column, using ethyl acetate-n-hexane (=1:1) as an eluantto give the titled compound (2.4 g, yield 63%) as white crystals.

Melting point: 156°-157° C.

IR spectrum ν_(max) ^(KBr) (cm⁻¹): 3200, 3090, 1740, 1690

MS spectrum: M⁺ 383

NMR spectrum (CDCl₃, TMS, δ): 2.03 (3H, s), 3.25 (2H, ABq), 4.06 (1H,dd), 4.93 (2H+1H, m), 6.83 (1H, m), 7.22 (1H, d), 8.44 (1H, s)

(ii) Preparation of 5-methyl-6-(4-pyridazinyl)-2H-1,4-thiazin-3(4H)-one

5-methyl-6-[1-(2,2,2-trichloroethoxycarbonyl)-1,4-dihydro-4-pyridazinyl]-2H-1,4-thiazin-3(4H)-one(2.4 g) was well mixed with sulfur sublimed (10.7 g) in a mortar and themixture was stirred at 140° C. for 1.5 hours and then was cooled toambient temperature. The obtained solid was ground and was extractedwith methanol. Methanol was removed under reduced pressure. The residuewas dissolved in 50 ml of 2N hydrochloric acid. The insoluble matter wasremoved by filtration and the filtrate was adjusted to pH 7.2 by 2Naqueous sodium hydroxide. The resulting precipitates were removed byfiltration. The filtrate was extracted with chloroform (20 ml×5 times)and the extract was evaporated to dryness. After combined with the abovesolid, the residue was recrystallized from methanol to give the titledcompound (0.3 g, yield 23%) as pale yellow plates.

Melting point: 231°-233° C.

IR spectrum ν_(max) ^(KBr) (cm⁻¹): 3200, 3050, 2900, 1670, 1600

MS spectrum: M⁺ 207

NMR spectrum (DMSO-d₆, TMS, δ): 1.99 (3H, s), 3.46 (2H, s), 7.65 (1H,dd), 9.20 (1H, dd), 9.25 (1H, dd), 10.18 (1H, s)

Example 3 (i) Preparation of intermediate:5-methyl-6-[1-(2,2,2-trichloroethoxycarbonyl)-3-chloro-1,4-dihydro-4-pyridinyl]-2H-1,4-thiazin-3(4H)-one

3-Chloropyridine (0.88 g), 2,2,2-trichloroethylchloroformate (1.33 ml)and 5-methyl-2H-1,4-thiazin-3(4H)-one (0.5 g) were treated in the samemanner as described in Example 2 (i) to give the titled compound (0.75g, yield 46.3%) as milky white crystals. Chloroform-methanol (=30:1) wasused as a developing eluant.

Melting point: 168.5°-171° C.

IR spectrum ν_(max) ^(KBr) (cm⁻¹): 3190, 3080, 2930, 1720, 1670, 1630

NMR spectrum (CDCl₃, TMS, δ): 2.07 (3H, s), 3.28 (2H, s), 4.39 (1H, d),4.93 (2H+1H, m), 7.10 (1H, d), 7.30 (1H, s), 8.38 (1H, s)

(ii) Preparation of5-methyl-6-(3-chloro-4-pyridinyl)-2H-1,4-thiazin-3(4H)-one

A mixture of5-methyl-6-[1-(2,2,2-trichloroethoxycarbonyl)-3-chloro-1,4-dihydro-4-pyridinyl]-2H-1,4-thiazin-3(4H)-one(0.25 g) and sulfur sublimed (0.125 g) in N,N-dimethylformamide (2 ml)was stirred at 160° C. for 5 hours. The solvent was removed underreduced pressure and the residue was extracted with 2N hydrochloricacid. The insoluble matter was removed by filtration and the filtratewas washed with ether and was adjusted to pH about 7.5 by 2N aqueoussodium hydroxide. The resulting precipitates were extracted withchloroform. The extract was dried over magnesium sulfate and wasevaporated to dryness. The residue was chromatographed on silica gel(Wakogel C-200) column, using chloroformmethanol (=30:1) as an eluant togive the titled compound (0.083 g, yield 57.8%) as milky white crystals.

Melting point: 169°-171° C.

IR spectrum ν_(max) ^(KBr) (cm.sup. -1): 3200, 3080, 2940, 1630, 1570,1350

NMR spectrum (CDCl₃, TMS, δ): 1.85 (3H, s), 3.49 (2H, s), 7.30 (1H, d),8.59 (1H, d), 8.76 (1H, s), 9.00 (1H, s)

Example 4 (i) Preparation of intermediate:5-methyl-6-[1-(2,2,2-trichloroethoxycarbonyl)-3-formyl-1,4-dihydro-4-pyridinyl]-2H-1,4-thiazin-3(4H)-one

2,2,2-Trichloroethylchloroformate (2.13 ml) was added dropwise to asolution of pyridine-3-aldehyde (1.66 g) in dry acetonitrile (50 ml)under ice-cooling, and the mixture was stirred for 0.5 hour.5-Methyl-2H-1,4-thiazin-3(4H)-one (1.0 g) was added to the mixture. Thereaction mixture was further stirred at ambient temperature for 1 hour.The solvent was removed under reduced pressure. The residue waschromatographed on silica gel (Wakogel C-200) column, using ethylacetate-n-hexane (=1:1) as an eluant. The eluant was recrystallized fromethanol to give the titled compound (1.4 g, yield 44%) as pale yellowcrystals.

Melting point: 154°-156° C.

IR spectrum ν_(max) ^(KBr) (cm⁻¹): 3220, 3050, 2200, 1720, 1660, 1610

NMR spectrum (CDCl₃, TMS, δ): 2.17 (3H, s), 3.17 (2H, s), 4.53 (1H, d),5.13 (2H+1H, s+dd), 7.13 (1H, d), 7.89 (1H, d), 8.23 (1H, s), 9.53 (1H,s)

(ii) Preparation of5-methyl-6-(3-formyl-4-pyridinyl)-2H-1,4-thiazin-3(4H)-one

A mixture of5-methyl-6-[1-(2,2,2-trichloroethoxycarbonyl)-3-formyl-1,4-dihydro-4-pyridinyl]-2H-1,4-thiazin-3(4H)-one(0.5 g) and sulfur (2.5 g) was stirred at 160° C. for 3 hours. Aftercooling, the solid was ground and was extracted with methanol usingSoxhlet extractor. Methanol was removed under reduced pressure. Theresidue was extracted with 40 ml of 2N hydrochloric acid. The insolublematter was removed by filtration and the filtrate was washed with etherand the water phase was adjusted to pH 7.5 by 2N aqueous sodiumhydroxide. The resulting precipitates were extracted with chloroform andwere dried. Chloroform was removed under reduced pressure and theresidue was purified by the preparative thin layer chromatography [TLCsilica gel plate 60F₂₅₄ (supplied by Merck & Co. Inc., U.S.A.), 20×20cm, thickness 1 mm, chloroform-methanol=40:1] to give the titledcompound (0.03 g, yield 10.6%) as pale yellow crystals.

Melting point: 152°-154° C.

IR spectrum ν_(max) ^(KBr) (cm⁻¹): 3180, 3060, 1660, 1620

NMR spectrum (CDCl₃, TMS, δ): 1.85 (3H, s), 3.52 (2H, s), 7.32 (1H, d),8.45 (1H, s), 8.80 (1H, d), 9.11 (1H, s), 10.23 (1H, s)

Example 5 (i) Preparation of intermediate:5-methyl-6-[1-(2,2,2-trichloroethoxy-carbonyl)-3-cyano-1,4-dihydro-4-pyridinyl]-2H-1,4-thiazin-3(4H)-one

A mixture of nicotinonitrile (1.62 g), 2,2,2-trichloroethylchloroformate(2.13 ml) and 5-methyl-2H-1,4-thiazin-3(4H)-one (1.0 g) was treated inthe same manner as described in Example 4 (i) to give the titledcompound (0.8 g, yield 25%) as pale yellow crystals. Chloroform-methanol(=20:1) was used as a developing eluant.

Melting point: 189°-191° C. (decomposition)

IR spectrum ν_(max) ^(KBr) (cm⁻¹): 3200, 3050, 1720, 1660, 1610

NMR spectrum (CDCl₃, TMS, δ): 2.08 (3H, s), 3.30 (2H, ABq), 4.36 (1H,d), 4.95 (2H+1H, m), 7.00 (1H, d), 7.62 (1H, s), 7.84 (1H, s)

(ii) Preparation of5-methyl-6-(3-cyano-4-pyridinyl)-2H-1,4-thiazin-3(4H)-one

A mixture of5-methyl-6-[1-(2,2,2-trichloroethoxycarbonyl)-3-cyano-1,4-dihydro-4-pyridinyl]-2H-1,4-thiazin-3(4H)-one(0.5 g) and sulfur sublimed (2.5 g) was treated in the same manner asdescribed in Example 4 (ii) to give the titled compound (0.03 g, yield10.6%) as pale orange powder. Chloroform-methanol (=20:1) was used as adeveloping eluant.

Melting point: 140°-142° C.

IR spectrum ν_(max) ^(KBr) (cm⁻¹): 3170, 3050, 2230, 1680 1600

NMR spectrum (CDCl₃, TMS, δ): 1.95 (3H, s), 3.50 (2H, s), 7.38 (1H, d),8.65 (1H, s), 8.90 (1H, d), 8.93 (1H, s)

Example 6 (i) Preparation of intermediate:5-methyl-6-[1-(2,2,2-trichloroethoxycarbonyl)-3-methoxycarbonyl-1,4-dihydro-4-pyridinyl]-2H-1,4-thiazin-3(4H)-one

A mixture of methylnicotinate (2.74 g),2,2,2-trichloroethylchloroformate (3.44 ml) and5-methyl-2H-1,4-thiazin-3(4H)-one (1.29 g) was treated in the samemanner as described in Example 2 (i) to give the titled compound (2.1 g,yield 48%) as pale yellow crystals. Ethyl acetate-n-hexane (=1:1) wasused as a developing eluant.

Melting point: 171°-172° C.

IR spectrum ν_(max) ^(KBr) (cm⁻¹): 3300, 1730, 1670, 1610

MS spectrum: M⁺ 440

NMR spectrum (CDCl₃, TMS, δ): 2.10 (3H, s), 3.16 (2H, s), 3.76 (3H, s),4.47 (1H, d), 4.90 (2H+1H, m), 7.00 (1H, d), 7.82 (1H, s), 8.09 (1H, s)

(ii) Preparation of intermediate:5-methyl-6-(1H-3-methoxycarbonyl-1,4-dihydro-4-pyridinyl)-2H-1,4-thiazin-3(4H)-one

Zinc powder (1.5 g) was added to a solution of5-methyl-6-[1-(2,2,2-trichloroethoxycarbonyl)-3-methoxycarbonyl-1,4-dihydro-4-pyridinyl]-2H-1,4-thiazin-3(4H)-one(2.1 g) in 50% THF (60 ml) and the mixture was stirred at 60° C. for 2hours and zinc powder (0.5 g) was added to the mixture gain and themixture was stirred for further 2 hours. The reaction mixture was cooledto ambient temperature, was filtered and was washed with 50% THF. Thefiltrate was extracted with benzene. The extract was washed with water,was dried over magnesium sulfate and the solvent was removed underreduced pressure to give the titled compound (0.76 g, yield 60%) as paleyellow crystals.

Melting point: 176°-177° C.

IR spectrum ν_(max) ^(KBr) (cm⁻¹): 3200, 1620, 1600

MS spectrum: M⁺ 266

NMR spectrum (DMSO-d₆, TMS, δ): 1.91 (3H, s), 3.05 (2H, ABq), 3.54 (3H,s), 4.39 (1H, d), 4.45 (1H, dd), 6.14 (1H, dd), 7.24 (1H, d), 8.30 (1H,s), 9.34 (1H, s)

(iii) preparation of5-methyl-6-(3-methoxycarbonyl-4-pyridinyl)-2H:1,4-thiazin-3(4H)-one

DDQ (0.65 g) was added to a solution of5-methyl-6-(1H-3-methoxycarbonyl-1,4-dihydro-4-pyridinyl)-2H-1,4-thiazin-3(4H)-one(0.76 g) in dry acetonitrile (30 ml) and the mixture was stirred at 50°C. for 2 hours. The mixture was cooled to ambient temperature and wasfiltered. The solvent was removed under reduced pressure. The residuewas chromatographed on silica gel (Wakogel C-200) column usingchloroform-methanol (=20:1) as an eluant and was recrystallized fromabsolute ethanol to give the titled compound (0.48 g, yield 64%) as paleyellow crystals.

Melting point: 177°-178° C.

IR spectrum ν_(max) ^(KBr) (cm⁻¹): 3300, 1710, 1680, 1620

MS spectrum: M⁺ 264

NMR spectrum (CDCl₃, TMS, δ): 1.83 (3H, s), 3.46 (2H, s), 3.94 (3H, s),7.21 (1H, d), 8.33 (1H, s), 8.72 (1H, d), 9.12 (1H, s)

Example 7 (i) Preparation of intermediate:5-methyl-6-[1-(2,2,2-trichloroethoxycarbonyl)-3-acetyl-1,4-dihydro-4-pyridinyl]-2H-1,4-thiazin-3(4H)-one

A mixture of 3-acetylpyridine (2.18 ml),2,2,2-trichloroethylchloroformate (3.44 ml) and5-methyl-2H-1,4-thiazin-3(4H)-one (1.29 g) was treated in the samemanner as described in Example 2 (i) to give the titled compound (1.77g, yield 42%) as pale yellow crystals. Ethyl acetate-n-hexane (=1:1) wasused as a developing eluant.

Melting point: 138°-140° C.

IR spectrum ν_(max) ^(KBr) (cm⁻¹): 3200, 3060, 2910, 1730, 1660

NMR spectrum (CDCl₃, TMS, δ):

2.13 (3H, s), 2.34 (3H, s), 3.12 (2H, ABq), 4.53 (1H, d), 4.86 (1H, m),5.02 (2H, m), 7.00 (1H, d), 7.60 (1H, s), 8.03 (1H, s)

(ii) Preparation of5-methyl-6-(3-acetyl-4-pyridinyl)-2H-1,4-thiazin-3(4H)-one

A mixture of5-methyl-6-[1-(2,2,2-trichloroethoxycarbonyl)-3-acetyl-1,4-dihydro-4-pyridinyl]-2H-1,4-thiazin-3(4H)-one(1.77 g) and sulfur sublimed (0.8 g) was treated in the same manner asdescribed in Example 3 (ii) to give the titled compound (0.08 g, yield7.8%) as pale yellow crystals. Ethyl acetate was used as a developingeluant.

Melting point: 155°-157° C.

IR spectrum ν_(max) ^(KBr) (cm⁻¹): 3200, 1680, 1620

NMR spectrum (CDCl₃, TMS, δ): 1.84 (3H, s), 2.61 (3, s), 3.43 (2H, s),7.23 (1H, d), 8.27 (1H, s), 8.69 (1H, d), 8.88 (1H, s)

Example 8 (i) Preparation of intermediate:5-methyl-6-[1-(2,2,2-trichloroethoxycarbonyl)-6-methoxy-b1,4-dihydro-4-quinolinyl]-2H-1,4-thiazin-3(4H)-one

A mixture of 6-methoxyquinoline (1.1 ml),2,2,2-trichloroethylchloroformate (1.4 ml) and5-methyl-2H-1,4-thiazin-3(4H)-one (0.52 g) was treated in the samemanner as described in Example 2 (i) to give the titled compound (0.6 g,yield 32%) as white crystals. n-Hexane-ethyl acetate (=3:2) was used asa developing eluant.

Melting point: 170°-171° C.

IR spectrum ν_(max) ^(KBr) (cm⁻¹): 3200, 3050, 2940, 1720, 1670

NMR spectrum (CDCl₃, TMS, δ): 2.13 (3H, s), 3.12 )2H, ABq), 3.79 (3H,s), 4.61 (1H, d), 4.92 (2H, s), 5.16 (1H, dd), 6.61 (1H, d), 6.84 (1H,dd), 7.20 (1H, d), 8.04 (1H, d), 8.06 (1H, s)

(ii) Preparation of5-methyl-6-(6-methoxy-4-quinolinyl)-2H-1,4-thiazin-3(4H)-one

A mixture of5-methyl-6-[1-(2,2,2-trichlorethoxycarbonyl)-6-methoxy-1,4-dihydro-4-quinolinyl]-2H-1,4-thiazin-3(4H)-one(0.6 g) and sulfur sublimed (0.3 g) was treated in the same manner asdescribed in Example 3 (ii) to give the titled compound (0.12 g, yield33%) as pale red crystals. Ethyl acetate was used as a developingeluant.

Melting point: 178°-179°C.

IR spectrum ν_(max) ^(KBr) (cm⁻¹): 3200, 3100, 2950, 1680,

NMR spectrum (CDCl₃, TMS, δ): 1.82 (3H, s), 3.55 (2H, ABq), 3.94 (3H,s), 7.15 (1H, d), 7.28 (1H, d), 7.41 (1H, dd), 8.06 (1H, d), 8.31 (1H,s), 8.78 (1H, d)

Example 9 (i) Preparation of intermediate:5-methyl-6-[1-(2,2,2-trichloroethoxy-carbonyl)-3-methyl-1,4-dihydro-4-pyridazinyl]2H-1,4-thiazin-3(4H)-one

A mixture of 3-methylpyridazine (1.82 ml),2,2,2-trichloroethylchloroformate (3.44 ml) and5-methyl-2H-1,4-thiazin-3(4H)-one (1.29 g) was treated in the samemanner as described in Example 2 (i) to give the titled compound (0.4 g,yield 10%) as white crystals. n-Hexane-ethyl acetate (=3:2) was used asa developing eluant.

Melting point: 186°-187° C.

IR spectrum ν_(max) ^(KBr) (cm⁻¹): 3200, 3070, 2950, 1720, 1670, 1635

NMR spectrum (DMSO-d₆, TMS, δ): 1.92 (3H, s), 1.98 (3H, s), 3.08 (1H,d), 3.25 (1H, d), 4.20 (1H, d), 4.94 (1H, dd), 5.03 (2H, s), 7.17 (1H,d), 9.64 (1H, s)

(ii) Preparation of5-methyl-6-(3-methyl-4-pyridazinyl)-2H-1,4-thiazin-3(4H)-one

A mixture of5-methyl-6-[1-(2,2,2-trichloroethoxycarbonyl)-3-methyl-1,4-dihydro-4-pyridazinyl]-2H-1,4-thiazin-3(4H)-one(0.4 g) and sulfur sublimed (0.2 g) was treated in the same manner asdescribed in Example 3 (ii) to give the titled compound (0.08 g, yield36%) as white crystals. Chloroform-methanol (=20:1) was used as adeveloping eluant.

Melting point: 186°-188° C.

IR spectrum ν_(max) ^(KBr) (cm⁻¹): 3200, 3050, 2900, 1670, 1620

NMR spectrum (CDCl₃, TMS, δ): 1.81 (3H, s), 2.75 (3H, s), 3.46 (2H, s),7.26 (1H, d), 8.24 (1H, s), 9.09 (1H, d)

Example 10 (i) Preparation of intermediate:5-methyl-6-[1-(2,2,2-trichloroethoxycarbonyl)-3-methyl-1,4-dihydro-4-pyridinyl]-2H-1,4-thiazin-3(4H)-one

A mixture of 3-methylpyridine (0.72 g),2,2,2-trichloroethylchloroformate (1.33 ml) and5-methyl-2H-1,4-thiazin-3(4H)-one (0.5 g) was treated in the same manneras described in Example 2 (i) to give the titled compound (0.49 g, yield31%) as milky white crystals. n-Hexane-ethyl acetate (=1:1) was used asa developing eluant.

Melting point: 149°-152° C.

IR spectrum ν_(max) ^(KBr) (cm⁻¹): 3190, 3070, 2930, 1720, 1670, 1630,1380, 1320

NMR spectrum (CDCl₃, TMS, δ): 1.65 (3H, s), 2.03 (3H, s), 3.21 (2H,ABq), 4.02 (1H, d), 4.74-4.96 (2H+1H, m), 6.80 (1H, d), 6.98 (1H, d),8.04 (1H, s)

(ii) Preparation of5-methyl-6-(3-methyl-4-pyridinyl)-2H-1,4-thiazin-3(4H)-one

A mixture of5-methyl-6-[1-(2,2,2-trichloroethoxycarbonyl)-3-methyl-1,4-dihydro-4-pyridinyl]-2H-1,4-thiazin-3(4H)-one(0.25 g) and sulfur sublimed (0.125 g) was treated in the same manner asdescribed in Example 3 (ii) to give the titled compound (0.118 g, yield86.3%) as pale brown crystals. Chloroform-methanol (=20:1) was used as adeveloping eluant.

Melting point: 185°-187° C.

IR spectrum ν_(max) ^(KBr) (cm⁻¹): 3040, 2850, 1670, 1630, 1590, 1330

NMR spectrum (CDCl₃, TMS, δ): 1.78 (3H, s), 2.31 (3H, s), 3.44 (2H, s),7.09 (1H, d), 8.44 (1H, d), 8.51 (1H, s), 8.58 (1H, s)

Example 11 (i) Preparation of intermediate:5-methyl-6-(3-ethoxycarbonyl-dihydro-2-thiazolyl)-2H-1,4-thiazin-3(4H)-one

Ethylchloroformate (3.6 g) was added dropwise to a solution of thiazole(5.7 g) in dichloromethane (72 ml) under ice-cooling, and the mixturewas stirred for 30 minutes. Then, 5-methyl-2H-1,4-thiazin-3(4H)-one (3.6g) was added dropwise to the mixture. The reaction mixture was furtherstirred at ambient temperature for 5 hours. The mixture was washed with2N hydrochloric acid and successively with water, was dried overanhydrous magnesium sulfate and the solvent was removed. The residue waschromatographed on silica gel (Wakogel C-200) column, using ethylacetate-n-hexane (=1:1) as an eluant and was recrystallized from ethanolto give the titled compound (1.9 g, yield 23.8%) as white needles.

Melting point: 146°-147° C.

IR spectrum ν_(max) ^(KBr) (cm⁻¹): 3220, 3130, 1700, 1680, 1640, 1600

(ii) Preparation of 5-methyl-6-(2-thiazolyl)-2H-1,4-thiazin-3(4H)-one

DDQ (0.16 g) was added to5-methyl-6-(3-ethoxycarbonyl-dihydro-2-thiazolyl)-2H-1,4-thiazin-3(4H)-one(0.2 g) in dichloromethane (5 ml) and the reaction mixture was stirredat ambient temperature for 1.5 hours. The resulting crystals werefiltrated, were washed with saturated aqueous calcium bicarbonate andsuccessively with water, was recrystallized from methanol to give thetitled compound (0.08 g, yield 54.0%) as white needles.

Melting point: 233°-235° C. (decomposition)

IR spectrum ν_(max) ^(KBr) (cm⁻¹): 3200, 3080, 1680, 1615

NMR spectrum (DMSO-d₆, TMS, δ): 2.4 (3H, s), 3.4 (2H, s), 7.7 (1H, d),7.9 (1H, d), 10.2 (1H, s)

Example 12 (i) Preparation of intermediate: ethyl thiolactate

Conc. sulfuric acid (2 ml) was added as catalist to a stirred solutionof thiolactic acid (25 g) in absolute ethanol (200 ml) and the solutionwas refluxed for 6 hours. After conclusion of reaction was checked bygas chromatography [column:FFAP, column temperature 100° C., carrier gasN₂ (20 ml/min)], ethanol was removed at atmospheric pressure. Theresulting solution was distillated under reduced pressure to give thetitled oily compound (19.1 g, yield 58%).

Boiling point: 52°-54° C./16 mmHg

NMR spectrum (CDCl₃, TMS, δ): 1.29 (3H, t), 1.54 (3H, d), 2.16 (1H, d),3.53 (1H, m), 4.20 (2H, q)

(ii) Preparation of intermediate: 2,5-dimethyl-2H-1,4-thiazin-3(4H)-one

Ethyl thiolactate (19.0 g) was added to aqueous ammonia (100 ml) and themixture was stirred under nitrogen atmosphere at ambient temperature for20 hours. The solvent was removed under reduced pressure and the residuewas ice-cooled to give thiolacticamide as white crystals.

These crystals are dissolved in absolute ethanol (100 ml) and added withtriethylamine (20 ml). A solution (40 ml) of chloroacetone (12 ml) inether was added dropwise to the mixture over about 2 hours underice-cooling. The reaction mixture was further stirred for 2 hours atambient temperature. The solvent was removed under reduced pressure at50° C. and the residue was added with acetone (150 ml) and was filtered.The filtrate was concentrated under reduced pressure and was added withabsolute ethanol (100 ml), was adjusted to pH 1-2 by p-toluenesulfonicacid, and was heated to 60°-70° C. for 30 minutes, and the solvent wasremoved under reduced pressure. The residue was chromatographed onsilica gel (Wakogel C-200) column, using ethyl acetate-n-hexane (=1:1)as an eluant to give the titled compound (3.9 g, yield 11%) as whitecrystals.

Melting point: 78°-80° C.

Elementary analysis values as: C₆ H₉ NOS; Calculated: C=50.32; H=6.33;N=9.78 (%); Found: C=50.06; H=6.47; N=9.62 (%)

IR spectrum ν_(max) ^(KBr) (cm⁻¹): 3200, 3100, 1670, 1630

NMR spectrum (CDCl₃, TMS, δ): 1.44 (3H, d), 1.95 (3H, s), 3.35 (1H, dd),5.21 (1H, s), 8.07 (1H, s)

(iii) Preparation of intermediate:2,5-dimethyl-6-[1-(2,2,2-trichloroethoxycarbonyl)-1,4-dihydro-4-pyridinyl]-2H-1,4-thiazin-3(4H)-one

2,2,2-Trichloroethylchloroformate (1.68 ml) was added dropwise to asolution of 2,5-dimethyl-2H-1,4-thiazin-3(4H)-one (1.43 g) and pyridine(1.6 ml) in acetonitrile (50 ml) under ice-cooling, and the solution wasstirred for 30 minutes at 0° C. The mixture was further stirred atambient temperature for 2 hours. The solvent was removed under reducedpressure. The residue was extracted with chloroform, was washed with 2Nhydrochloric acid and successively with water and was dried overmagnesium sulfate. The solvent was removed and the residue waschromatographed on silica gel (Wakogel C-200) column, using ethylacetate-n-hexane (=1:1) as an eluant. The eluate was washed with etherto give the titled compound (1.68 g, yield 42%) as pale yellow crystals.

Melting point: 140°-142° C.

Elementary analysis values as: C₁₄ H₁₅ N₂ O₃ SCl₃ ; Calculated: C=42.28;H=3.80; N=7.04 (%); Found: C=42.33; H=3.89; N=7.17 (%)

IR spectrum ν_(max) ^(KBr) (cm⁻¹): 3200, 3080, 2950, 1720, 1670, 1630

NMR spectrum (CDCl₃, TMS, δ): 1.40 (3H, d), 1.98 (3H, s), 3.33 (1H, q),4.16 (1H, m), 4.77 (2H, d), 4.92 (2H, d), 6.95 (2H, d), 7.75 (1H, s)

(iv) Preparation of2,5-dimethyl-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-one

Sulfur sublimed (0.7 g) was added to a solution of2,5-dimethyl-6-[1-(2,2,2-trichloroethoxycarbonyl)-1,4-dihydro-4-pyridinyl]-2H-1,4-thiazin-3(4H)-one(1.5 g) in dimethylformamide (20 ml) and the mixture was stirred at 140°C. for 2 hours. Then, the mixture was allowed to cool to ambienttemperature and the solvent was removed under reduced pressure. Theresidue was dissolved in 2N hydrochloric acid and the insoluble matterwas removed by filtration. The filtrate was adjusted to pH 7-8 by 2Naqueous sodium hydroxide. The precipitated crude crystals werechromatographed on silica gel (Wakogel C-200) column, usingchloroform-methanol (=20:1) as an eluant to give pale yellow crystals.These crude crystals were dissolved in chloroform, were washed withwater and were dried over magnesium sulfate. The solvent was removedunder reduced pressure to give the titled compound (0.43 g, yield 52%)as white crystals.

Melting point: 144°-146° C.

Elementary analysis values as: C₁₁ H₁₂ N₂ OS; Calculated: C=59.97;H=5.49; N=12.71 (%); Found: C=59.76; H=5.55; N=12.55; (%)

IR spectrum ν_(max) ^(KBr) (cm⁻¹): 3200, 3090, 2950, 1680, 1620

NMR spectrum (CDCl₃, TMS, δ): 1.53 (3H, d), 2.05 (3H, s), 3.53 (1H, q),7.28 (2H, dd), 7.40 (1H, s), 8.61 (2H, dx2)

Example 13 (i) Preparation of intermediate: δ-bromo-n-butylamide

δ-Bromo-n-butylbromide (9.7 ml) was slowly added dropwise to a conc.aqueous ammonia (28%, 33 ml) at less than -10° C. while being stirredviolently. The precipitated white crystals were suspended in water, wereextracted with ethyl acetate. The extract was washed with water, wasdried over magnesium sulfate. The solvent was removed under reducedpressure to give the titled compound (9.57 g, yield 72%) as whitecrystals.

Melting point: 109°-111° C.

IR spectrum ν_(max) ^(KBr) (cm⁻¹): 3360, 3180, 1670

NMR spectrum (CDCl₃, TMS, δ): 1.03 (3H, t), 2.13 (2H, m), 4.30 (1H, t),6.50 (2H, s)

(ii) Preparation of intermediate:2-ethyl-5-methyl-2H-1,4-thiazin-3(4H)-one

α-Bromo-n-butylamide (1.66 g) and potassium xanthogenate (1.60 g) weresuspended in acetone (20 ml) and the suspension was stirred at ambienttemperature for 2 hours, then the mixture was filtered. The filtrate wascondenced to give oily product. Benzen (15 ml) and morphorine (1.7 ml)were added to the oily product. The mixture was refluxed for 2 hoursunder heating and was allowed to cool. The solvent was removed underreduced pressure to give α-mercapto-n-butylamide. Without purification,this amide is added with absolute ethanol (15 ml) and triethylamine (1.3ml) and then chloroacetone (0.8 ml) in ether (1.0 ml) was added dropwiseto the solution under ice-cooling for 2 hours. Then, the reactionmixture was stirred at ambient temperature for overnight. The solventwas removed under reduced pressure to give oily product. Acetone (20 ml)was added to the oily product and the mixture was filtered for removalof the precipitated crystals. Further, the crystals were washed withacetone (10 ml) and the mother liquor was condenced, was added withabsolute ethanol (10 ml), was adjusted to pH 1-2 by p-toluenesulfonicacid, was heated at 70° C. for 30 minutes. The solvent was removed underreduced pressure and the residue was extracted with ethyl acetate. Theextract was washed with water, was dried over magnesium sulfate, and thesolvent was removed under reduced pressure. The residue waschromatographed on silica gel (Wakogel C-200) column, using ethylacetate-n-hexane (=1:3) as an eluant to give the titled compound (1.21g, yield 77%) as white crystals.

Melting point: 69°-71° C.

Elementary analysis values as: C₇ H₁₁ NOS; Calculated: C=53.47; H=7.05;N=8.90 (%); Found: C=53.51; H=7.28; N=8.86 (%);

IR spectrum ν_(max) ^(KBr) (cm⁻¹): 3200, 3100, 2950, 1680

NMR spectrum (CDCl₃, TMS, δ): 1.04 (3H, dd), 1.65 (1H, m), 1.90 (1H, m),1.93 (3H, s), 3.12 (1H, m), 5.14 (1H, s), 7.92 (1H, s)

(iii) Preparation of2-ethyl-5-methyl-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-one

2,2,2-Trichloroethylchloroformate (1.0 ml) was added dropwise to asolution of 2-ethyl-5-methyl-2H-1,4-thiazin-3(4H)-one (0.94 g) andpyridine (0.96 ml) in acetonitrile (30 ml) under ice-cooling, and themixture was stirred at 0° C. for 30 minutes. Then the mixture wasfurther stirred at ambient temperature for 18 hours. The solvent wasremoved under reduced pressure and the residue was extracted with ethylacetate, was washed with water, 2N hydrochloric acid and water in theorder named, and was dried over magnesium sulfate. The solvent wasremoved under reduced pressure to give2-ethyl-5-methyl-6-[1-(2,2,2-trichloroethoxycarbonyl)-1,4-dihydro-4-pyridinyl]-2H-1,4-thiazin-3(4H)-one(2.0 g) as pale yellow oily product.

This oily product was dissolved in dimethylformamide (20 ml), was addedwith sulfur sublimed (0.6 g) and was stirred at 140° C. for 3 hours. Themixture was allowed to cool and the solvent was removed under reducedpressure. The residue was dissolved in 2N hydrochloric acid. Theinsoluble matter was removed by filtration and the filtrate was washedwith ether and the water phase was adjusted to neutralization by 2Naqueous sodium hydroxide, was extracted with chloroform. The extract waswashed with water and was dried over magnsium sulfate. The solvent wasremoved under reduced pressure and the residue was chromatographed onsilica gel (Wakogel C-200) column, using chloroform-methanol (=20:1) asan eluant. The eluate was recrystallized from aqueous solution of 30%ethanol to give the titled compound (0.3 g, yield 21%) as pale yellowcrystals.

Melting point: 121°-123° C.

IR spectrum ν_(max) ^(KBr) (cm¹): 3210, 3100, 2960, 1670

NMR spectrum (CDCl₃, TMS, δ): 1.14 (3H, t), 1.76 (1H, m), 1.99 (1H, m),3.28 (1H, dd), 7.27 (2H, dd), 8.52 (1H, s), 8.61 (2H, dx2)

Example 14 (i) Preparation of intermediate:5-methyl-6-[1-(2,2,2-trichloroethoxycarbonyl)-1,4-dihydro-4-pyridinyl]-2H-1,4-thiazin-3(4H)-one

2,2,2-Trichloroethylchloroformate (64 ml) was added dropwise to asuspension of 5-methyl-2H-1,4-thiazin-3(4H)-one (50 g) and acetonitrile(500 ml) in pyridine (75 ml) under ice/water-cooling. The reactionmixture was further stirred at ambient temperature for 1 hour. Then, themixture was added with ice water (about 1.5 l), was stirred for a whileand was filtered. The filtration was recrystallized from ethanol to givethe titled compound (120 g, yield 80.7%) as pale yellow prisms.

Melting point: 158°-160° C.

Elementary analysis values as: C₁₃ H₁₃ N₂ O₃ SCl₃ ; Calculated: C=40.69,H=3.41; N=7.29 (%); Found: C=40.62; H=3.37; N=7.02 (%)

IR spectrum ν_(max) ^(KBr) (cm⁻¹): 3200, 3100, 1720, 1670, 1630

MS spectrum: M⁺ 382

NMR spectrum (CDCl₃, TMS, δ): 1.986 (3H, s), 3.229 (2H, s), 4.161 (1H,m), 4.800 (4H, m), 6.970 (2H, d), 7.264 (1H, b)

(ii) Preparation of 5-methyl-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-one

5-methyl-6-[1-(2,2,2-trichloroethoxycarbonyl)-1,4-dihydro-4-pyridinyl]-2H-1,4-thiazin-3(4H)-one(2.14 g) was mixed well with sulfur sublimed (10.7 g) in a mortar andthe mixture was stirred at 140° C. for 1.5 hours. Then, the mixture wascooled to ambient temperature. The obtained solid was ground and wasextracted with methanol using Soxhlet extractor. Methanol was removedunder reduced pressure. The residue was dissolved in 50 ml of 2Nhydrochloric acid. The insoluble matter was removed by filtration andthe filtrate was adjusted to pH 7.2 by 2N aqueous sodium hydroxide. Theresulting precipitates were collected by filtration and the filtrate wasextracted with chloroform (20 ml×5 times) and was evaporated to dryness.After combined with the above solid, the residue was recrystallized fromisopropanol to give the titled compound (0.88 g, yield 76.5%) as paleyellow plates.

Melting point: 187°-188.5° C.

Elementary analysis values as: C₁₀ H₁₀ N₂ OS; Calculated: C=58.22;H=4.88; N=13.58 (%); Found: C=58.48; H=4.99; N=13.53 (%)

IR spectrum ν_(max) ^(KBr) (cm⁻¹): 3200, 3050, 1680, 1580

MS spectrum: M⁺ 206

NMR spectrum (CDCl₃, TMS, δ): 2.056 (3H, s), 3.437 (2H, s), 7.280 (2H,d), 8.610 (2H, d), 8.700 (1H, d)

Example 15 Preparation of2-methoxy-5-methyl-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-one

m-Chloroperbenzoic acid (12 g) was added gradually to a stirredsuspension of 5-methyl-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-one (10 g)in methanol (400 ml) under ice/water-cooling. The reaction mixture wasfurther stirred at ambient temperature for 3 days. The solvent wasremoved under reduced pressure and the residue was extracted with ethylacetate, was washed with saturated sodium bicarbonate aqueous solutionand successively with water and was dried over magnesium sulfate. Thesolvent was removed under reduced pressure and the residue was dissolvedin chloroform (about 50 ml) and was chromatographed on activated alumina(200 g, about 300 mesh, manufactured by Wako Pure Chemical Industries,Ltd.) cloumn, using chloroform as an eluant. The solvent was removedunder reduced pressure and the residue was crystallized from ether togive the titled compound (6 g, yield 51.7%) as pale yellow powder.

Melting point: 133.5°-135° C.

IR spectrum ν_(max) ^(KBr) (cm⁻¹): 3200, 3050, 1690, 1610, 1590

NMR spectrum (CDCl₃, TMS, δ): 2.07 (3H, s), 3.55 (3H, s), 4.90 (1H, s),7.27 (2H, dd), 8.62 (2H, dx2) 9.10 (1H, s)

Example 16 Preparation of2,2-dimethoxy-5-methyl-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-one

m-Chloroperbenzoic acid (2.8 g) was added to a stirred solution of 2-methoxy-5-methyl-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-one (2.7 g) inmethanol (100 ml) under ice/water-cooling. The reaction mixture wasfurther stirred at ambient temperature for 2 hours. Methanol was removedunder reduced pressure and the residue was dissolved in ethyl acetate,was washed with saturated sodium bicarbonate aqueous solution andsuccessively with water, and was dried over magnesium sulfate. Ethylacetate was removed under reduced pressure and the residue wascrystallized from ether to give the titled compound (2 g, yield 66.7%)as pale yellow powder.

Melting point: 154°-155° C.

NMR spectrum (CDCl₃, TMS, δ): 2.03 (3H, s), 3.59 (6H, s), 7.25 (2H, dd),8.43 (1H, s), 8.62 (2H, dx2)

Example 17 (i) Preparation of5-methyl-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-one

Zinc powder (1.7 g) was added to a solution of5-methyl-6-[1-(2,2,2-trichloroethoxycarbonyl)-1,4-dihydro-4-pyridinyl]-2H-1,4-thiazin-3(4H)-one(1g) in formic acid (14 ml) and the mixture was stirred at ambienttemperature for 3 hours. The mixture was filtered and the filtrate wasevaporated to dryness. The residue was dissolved in water (30 ml), wasadjusted to pH 7.0 by 1N aqueous sodium hydroxide, was extracted withchloroform and was dried over magnesium sulfate. Chloroform was removedand the residue was purified by the preparative thin layerchromatography [Merck TLC plate, silica gel 60F₂₅₄ (supplied by Merck &Co. Inc., U.S.A.), 20×20 cm, thickness=1 mm, developing solvent;chloroform/methanol=20:1] to give the titled compound (0.2 g, yield37.1%) as pale yellow plates. The physiocochemical properties were asdescribed above.

(ii) Preparation of intermediate:2-(3-chlorobenzoyloxy)-5-methyl-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-one

m-Chloroperbenzoic acid (8.97 g, 70% purity) was added to a solution of5-methyl-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-one (5.0 g) indichloromethane (120 ml) under ice/water-cooling and the mixture wasstirred for 10 minutes under ice/water-cooling. The mixture was washedwith saturated sodium bicarbonate aqueous solution (2 times) andsuccessively with water (1 time) and was dried over magnsium sulfate.The solvent was removed under reduced pressure and the residue wasrecrystallized from ether-petrolem ether to give the titled compound(3.29 g, yield 37.6%) as pale yellow needles.

Melting point: 142°-143° C.

IR spectrum ν_(max) ^(KBr) (cm⁻¹): 3180, 3080, 2920, 1720, 1670, 1620,1590

NMR spectrum (CDCl₃, TMS, δ): 2.19 (3H, s), 6.60 (1H, s), 7.28 (2H, dd),7.47-8.23 (4H, m), 8.69 (2H, dx2), 9.78 (1H, s)

(iii) Preparation of2-amino-5-methyl-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-one

Ammonium carbonate (0.6 g) was added to a solution of2-(3-chlorobenzoyloxy)-5-methyl-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-one(0.4 g) in acetonitrile (20 ml). The mixture was stirred at ambienttemperature for 3 days, was filtered and the filtrate was evaporated todryness. The residue was chromatographed on silica gel (Wakogel C-200)column, using chloroform-methanol (=20:1) as an eluant to give thetitled compound (0.1 g, yield 40.7%).

IR spectrum ν_(max) ^(KBr) (cm⁻¹): 3370, 3300, 3200, 3060, 1665, 1610,1580

NMR spectrum (CDCl₃, TMS, δ): 2.70 (5H, s), 4.68 (1H, s), 7.28 (2H, dd),8.55 (1H, s), 8.62 (2H, dx2)

p-Toluenesulfonic acid hydrate (0.19 g) was added to a solution of thetitled compound in methanol (10 ml) and the mixture was stirred atambient temperature for 0.5 hour. Methanol is removed under reducedpressure and the residue was crystallized from acetone to givep-tosylate as pale yellow powder.

Melting point: 213°-217° C. (decomposition)

Example 18 Preparation of2-diethylamino-5-methyl-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-onehydrochloride

Diethylamine (2.58 ml) was added to a solution of2-(3-chlorobenzoyloxy)-5-methyl-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-one(0.9 g) in dry dichloromethane (12 ml) and the mixture was stirred atambient temperature for 21 hours. The solvent was removed under reducedpressure and the residue was dissolved in ethyl acetate, was washed withsaturated sodium bicarbonate aqueous solution and successively withwater and was dried over magnesium sulfate. The solvent was removedunder reduced pressure and the residue was chromatographed on silica gel(Wakogel C-200) column, using chloroform-methanol (=20:1) as an eluantto give pale yellow oily product. The oily product was dissolved inmethanol and was adjusted to pH 2 by 2N hydrochloric acid. The solventwas removed under reduced pressure and the residue was washed with THFand allowed to stand to give the titled compound (0.685 g, yield 78.4%)as yellow crystals.

Melting point: over 240° C. (decomposition)

IR spectrum ν_(max) ^(KBr) (cm⁻¹): 3050, 2890, 2420, 2070, 1680, 1605

NMR spectrum (DMSO-d₆, TMS, δ): 1.21 (6H, m), 2.10 (3H, s), 3.08 (4H,m), 5.37 (1H, s), 8.08 (2H, d), 8.86 (2H, d), 11.10 (1H, s)

Example 19 to Example 22 were treated in the same manner as described inExample 18.

Example 19 Preparation of5-methyl-2-methylamino-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-one

2-(3-Chlorobenzoyloxy)-5-methyl-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-oneand methylamine were reacted to give the titled compound as pale brownneedles.

Melting point: 170°-172° C. (decomposition)

IR spectrum ν_(max) ^(KBr) (cm⁻¹): 3310, 3220, 3090, 2940, 2800, 1690,1640, 1600

NMR spectrum (CDC1₃, TMS, δ): 1.82 (1H, s), 2.08 (3H, s), 2.62 (3H, s),4.43 (1H, s), 7.25 (2H, dd), 8.62 (2H, dx2), 9.21 (1H, s)

Example 20 Preparation of5-methyl-2-morphorino-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-one

2-(3-Chlorobenzoyloxy)-5-methyl-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-oneand morphorine were reacted to give the titled compound as pale browncrystals.

Melting point: 166°-167° C.

IR spectrum ν_(max) ^(KBr) (cm⁻¹): 3225, 3075, 2860, 2840, 1690, 1645,1625

NMR spectrum (CDC1₃, TMS, δ): 2.03 (3H, s), 2.57-2.93 (4H, m), 3.77 (4H,t), 4.64 (1H, s), 7.31 (2H, dd), 8.64 (2H, dx2), 9.83 (1H, s)

Example 21 Preparation of5-methyl-2-piperidino-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-onehydrochloride

2-(3-Chlorobenzoyloxy)-5-methyl-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-oneand piperidine were reacted. The resultant compound was added withhydrochloric acid and was recrystallized from ethanol to give the titledcompound as yellowish brown crystals.

Melting point: 228.5° C. (decomposition)

IR spectrum ν_(max) ^(KBr) (cm⁻¹): 3040, 2925, 2880, 2475, 2070, 1980,1850, 1680, 1620

NMR spectrum (DMSO-d₆, TMS, δ): 1.47 (2H, m), 1.72 (4H, m), 2.09 (3H,s), 2.78-3.12 (4H, m), 5.23 (1H, s), 8.06 (2H, dd), 8.85 (2H, dx2),10.98 (1H, s)

Example 22 Preparation of5-methyl-2-phenylamino-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-one

2-(3-Chlorobenzoyloxy)-5-methyl-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-oneand aniline were reacted to give the titled compound as pale yellowcrystals.

Melting point: 162°-165° C.

IR spectrum ν_(max) ^(KBr) (cm⁻¹): 3400, 3270, 3050, 2850, 2720, 1690,1625, 1600

NMR spectrum (DMSO-d₆, TMS, δ): 2.00 (3H, s), 5.37 (1H, d), 6.38 (1H,d), 6.68-7.17 (5H, m), 7.20 (2H, dd), 8.50 (2H, dx2), 10.25 (1H, s)

Example 23 Preparation of2-hydroxy-5-methyl-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-one

(i)2-(3-Chlorobenzoyloxy)-5-methyl-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-one(1.37 g) and water (1 ml) were dissolved in acetone (20 ml) and themixture was stirred at 70° C. for 44 hours. The mixture waschromatographed on silica gel (Wakogel C-200) column, usingchloroform-methanol (=30:1) as an eluant to give the titled compound(0.16 g, yield 19.1%) as red needles.

Melting point: 214°-214.5° C.

IR spectrum ν_(max) ^(KBr) (cm⁻¹): 3430, 3180, 3030, 2920, 1660, 1610,1580

MS spectrum: M⁺ 222

NMR spectrum (DMSO-d₆, TMS, δ): 1.94 (3H, s), 5.13 (1H, d), 6.93 (1H,d), 7.33 (2H, dd), 8.55 (2H, dx2), 10.11 (1H, s)

(ii) m-Chloroperbenzoic acid (0.216 g) was added to5-methyl-2H-1,4-thiazin-3(4H)-one (0.129 g) in dry acetone (4 ml) underice-cooling and the mixture was stirred for 2 hours. Water was added tothe mixture and the solution was stirred for 30 minutes. Then, thereaction mixture was further stirred at ambient temperature for 3 hours.The solvent was removed under reduced pressure and the residue waschromatographed on silica gel (Wakogel C-200) column, using ethylacetate-n-hexane (=2:1) as an eluant to give2-hydroxy-5-methyl-2H-1,4-thiazin-3(4H)-one (0.068 g, yield 46.9%) aswhite crystals.

Melting point: 166.5°-168° C.

IR spectrum ν_(max) ^(KBr) (cm⁻¹): 3260, 3190, 3080, 2950, 1655, 1635

NMR spectrum (DMSO-d₆, TMS, δ): 1.86 (3H, s), 4.96 (1H, d), 5.20 (1H,s), 6.62 (1H, d), 9.77 (1H, s)

A mixture of pyridine, 2,2,2-trichloroethylchloroformate and2-hydroxy-5-methyl-2H-1,4-thiazin-3(4H)-one was treated in the samemanner as described in Example 6. The residue was recrystallized fromethanol to give the titled compound as pale yellow crystals.

Example 24 Preparation of2-(4-hydroxyphenyl)-5-methyl-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-one

Silica gel (Wakogel C-200, 40 mg) was added as catalyst to a solution of2-(3-chlorobenzoyloxy)-5-methyl-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-one(0.98 g) and phenol (0.51 g) in acetonitrile (20 ml) and the mixture wasstirred at 50° C. for 35 hours. The mixture was chromatographed onsilica gel (Wakogel C-200) column, using chloroform-acetonitrile (=5:1)as an eluant. The residue was recrystallized from ethanol to give thetitled compound (0.19 g, yield 23.4%) as pale yellow powder.

Melting point: 198°-200° C.

IR spectrum ν_(max) ^(KBr) (cm⁻¹): 3380, 3190, 3050, 3400, 1660, 1620,1590

NMR spectrum (DMSO-d₆, TMS, δ): 2.01 (3H, s), 4.82 (1H, s), 6.76-7.18(4H, m), 7.13 (2H, dd), 8.49 (2H, dx2), 9.95 (1H, s), 10.36 (1H, s)

Example 25 Preparation of2-(2-furyl)-5-methyl-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-one

Silica gel (Wakogel C-200, 0.03 g) was added as catalyst to a solutionof2-(3-chlorobenzoyloxy)-5-methyl-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-one(0.79 g) and furan (0.30 g) in acetonitrile (30 ml) and the mixture wasstirred at 50° C. for 35 hours. The mixture was chromatographed onsilica gel (Wakogel C-200) column, using acetonitrile as an eluant. Theresidue was recrystallized from acetonitrile to give the titled compound(0.23 g, yield 37.7%) as pale orange crystals.

Melting point: 178°-179.5° C.

IR spectrum ν_(max) ^(KBr) (cm⁻¹): 3030, 2820, 1650, 1590, 1330

NMR spectrum (CDCl₃, TMS, δ): 2.04 (3H, s), 4.72 (1H, s), 6.30 (1H, d),6.37 (1H, t), 7.14 (2H, dd), 7.44 (1H, d), 8.18 (1H, s), 8.57 (2H, dx2)

CAPABILITY OF EXPLOITATION IN INDUSTRY

As is apparent from the foregoing description, the novel 1,4-thiazinederivative of the present invention is a compound not described in anyliterature, capable of increasing contractile force of cardiac muscleand having low acute toxicity so that it is effective in curing andpreventing heart diseases.

The process for preparation of the 1,4-thiazine derivative according tothe present invention is advantageous from the industrial viewpointbecause it may be prepared from relatively easily available startingcompounds in high yield by a relatively easy operation.

What is claimed is:
 1. A 1,4-thiazine derivative represented by theformula I and pharmaceutically acceptable acid addition salt thereof:##STR33## wherein R₁ and R₂ represent respectively hydrogen atom, loweralkyl group, lower alkoxy group, unsubstituted amino group, loweralkyl-amino group, aryl-amino group, wherein the aryl-amino is one ofphenyl-amino, tolyl-amino, xylyl-amino, mesitylamino, cumenyl-amino orbiphenyl-amino which may be unsubstituted or may be substituted withlower alkyl, lower alkoxy, halogeno, aldehyde, acyl, cyano, nitro orhydroxy, hydroxy group, aryl group wherein the aryl is one of phenyl,tolyl, xylyl, mesityl, cumenyl or biphenyl which may be unsubstituted ormay be substituted with lower alkyl, lower alkoxy, halogeno, aldehyde,acyl, cyano, nitro or hydroxy, or 5- or 6-membered heterocyclic residue;wherein the residue is furyl, thienyl, pyrrolyl, pyrano, pyridinyl,pyridazino, pyrimidino, piperidino, piperazino or morpholino;R₃ and R₄represent hydrogen atom or lower alkyl group; and R₅ representsN-containing heterocyclic residue wherein said residue is one ofpyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl,iso-quinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazainyl,acridinyl, thiazolyl, piperidinyl, piperazinyl or morpholinyl which maybe unsubstituted or may be substituted with lower alkyl, lower alkoxy,halogeno, aldehyde, acyl, cyano, nitro, hydroxy or lower alkoxycarbonyl,and is not pyridinyl group when R₁ and R₂ represent hydrogen atom and R₃and R₄ represent hydrogen atom or lower alkyl group.
 2. 1.4-thiazinederivative represented by the formula I and pharmaceutically acceptableacid addition salt thereof according to claim 1 wherein R₁ and R₂ arehydrogen atom.
 3. A 1,4-thiazine derivative represented by the formula Iand pharmaceutically acceptable acid addition salt thereof according toclaim 1 wherein R₁ and R₂ are methyl group or ethyl group.
 4. A1,4-thiazine derivative represented by the formula I andpharmaceutically acceptable acid addition salt thereof according toclaim 1 wherein R₁ and R₂ are amino group.
 5. A 1,4-thiazine derivativerepresented by the formula I and pharmaceutically acceptable acidaddition salt thereof according to claim 1 wherein R₁ and R₂ aremethylamino group or diethylamino group.
 6. A 1,4-thiazine derivativerepresented by the formula I and pharmaceutically acceptable acidaddition salt thereof according to claim 1 wherein R₁ and R₂ arephenylamino group.
 7. A 1,4-thiazine derivative represented by theformula I and pharmaceutically acceptable acid addition salt thereofaccording to claim 1 wherein R₁ and R₂ are hydroxy group.
 8. A1,4-thiazine derivative represented by the formula I andpharmaceutically acceptable acid addition salt thereof according toclaim 1 wherein R₁ and R₂ are phenyl group or hydroxyphenyl group.
 9. A1,4-thiazine derivative represented by the formula I andpharmaceutically acceptable acid addition salt thereof according toclaim 1 wherein R₁ and R₂ are furyl group, piperidino group ormorphorino group.
 10. A 1,4-thiazine derivative represented by theformula I and pharmaceutically acceptable acid addition salt thereofaccording to claim 1 wherein R₃ is hydrogen atom.
 11. A 1,4-thiazinederivative represented by the formula I and pharmaceutically acceptableacid addition salt thereof according to claim 1 wherein R₄ is methylgroup.
 12. A 1,4-thiazine derivative represented by the formula I andpharmaceutically acceptable acid addition salt thereof according toclaim 1 wherein R₅ is pyridinyl, pyridazinyl, quinolinyl, thiazolyl,methylpyridinyl, chloropyridinyl, formylpyridinyl, cyanopyridinyl,acetylpyridinyl, methoxyquinolinyl, methylpyridazinyl ormethoxycarbonylpyridinyl.
 13. A 1,4-thiazine derivative represented bythe formula I and pharmaceutically acceptable acid addition salt thereofaccording to claim 1 wherein said novel 1,4-thiazine derivative is5-methyl-6-(4-quinolinyl)-2H-1,4-thiazin-3(4H)-one.
 14. A 1,4-thiazinederivative represented by the formula I and pharmaceutically acceptableacid addition salt thereof according to claim 1 wherein said novel1,4-thiazine derivative is5-methyl-6-(4-pyridazinyl)-2H-1,4-thiazin-3(4H)-one.
 15. A 1,4-thiazinederivative represented by the formula I and pharmaceutically acceptableacid addition salt thereof according to claim 1 wherein said novel1,4-thiazine derivative is2,5-dimethyl-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-one.
 16. A1,4-thiazine derivative represented by the formula I andpharmaceutically acceptable acid addition salt thereof according toclaim 1 wherein said novel 1,4-thiazine derivative is2-ethyl-5-methyl-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-one.
 17. A1,4-thiazine derivative represented by the formula I andpharmaceutically acceptable acid additon salt thereof according to claim1 wherein said novel 1,4-thiazine derivative is5-methyl-6-(3-chloro-4-pyridinyl)-2H-1,4-thiazin-3(4H)-one.
 18. A1,4-thiazine derivative represented by the formula I andpharmaceutically acceptable acid addition salt thereof according toclaim 1 wherein said novel 1,4-thiazine derivative is5-methyl-6-(3-formyl-4-pyridinyl)-2H-1,4-thiazin-3(4H)-one.
 19. A1,4-thiazine derivative represented by the formula I andpharmaceutically acceptable acid addition salt thereof according toclaim 1 wherein said novel 1,4-thiazine derivative is5-methyl-6-(3-cyano-4-pyridinyl)-2H-1,4-thiazin-3(4H)-one.
 20. A1,4-thiazine derivative represented by the formula I andpharmaceutically acceptable acid addition salt thereof according toclaim 1 wherein said novel 1,4-thiazine derivative is5-methyl-2-methylamino-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-one.
 21. A1,4-thiazine derivative represented by the formula I andpharmaceutically acceptable acid addition salt thereof according toclaim 1 wherein said novel 1,4-thiazine derivative is2-hydroxyphenyl-5-methyl-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-one.
 22. A1,4-thiazine derivative represented by the formula I andpharmaceutically acceptable acid addition salt thereof according toclaim 1 wherein said novel 1,4-thiazine derivative is5-methyl-2-morpholino-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-one.
 23. Acardiotonic agent comprising a pharmaceutically acceptable excipient andan effective amount of a 1,4-thiazine derivative representated by theformula I or pharmaceutically acceptable acid addition salt thereof:##STR34## wherein R₁ and R₂ represent respectively hydrogen atom, loweralkyl group, lower alkoxy group, unsubstituted amino group, loweralkyl-amino group, aryl-amino group, wherein the aryl-amino is one ofphenyl-amino, tolyl-amino, xylyl-amino, mesityl-amino, cumenyl-amino orbiphenyl-amino which may be unsubstituted or may be substituted withlower alkyl, lower alkoxy, halogeno, aldehyde, acyl, cyano, nitro orhydroxy, hydroxy group, aryl group wherein the aryl is one of phenyl,tolyl, xylyl, mesityl, cumenyl or bipheynyl which may be unsubstitutedor may be substituted with lower alkyl, lower alkoxy, halogeno,aldehyde, acyl, cyano, nitro or hydroxy, or 5- or 6-memberedheterocyclic residue; wherein the residue is furyl, thienyl, pyrrolyl,pyrano, pyridinyl, pyridazino, pyrimidino, piperidino, piperazino ormorpholino;R₃ and R₄ represent hydrogen atom or lower alkyl group; andR₅ represents N-containing heterocyclic residue wherein said residue isone of pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl,iso-quinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazainyl,acridinyl, thiazolyl, piperidinyl, piperazinyl or morpholinyl which maybe unsubstituted or may be substituted with lower alkyl, lower alkoxy,halogeno, aldehyde, acyl, cyano, nitro, hydroxy or lower alkoxycarbonyl,and is not pyridinyl group when R₁ and R₂ represent hydrogen atom and R₃and R₄ represent hydrogen atom or lower alkyl group.
 24. A cardiotonicagent according to claim 23 wherein the 1,4-thiazine derivative is5-methyl-6-(4-quinolinyl)-2H-1,4-thiazin-3(4H)-one.
 25. A cardiotonicagent according to claim 23 wherein the 1,4-thiazine derivative is5-methyl-6-(4-pyridazinyl)-2H-1,4-thiazin-3(4H)-one.
 26. A cardiotonicagent according to claim 23 wherein the 1,4-thiazine derivative is2,5-dimethyl-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-one.
 27. A cardiotonicagent according to claim 23 wherein the 1,4-thiazine derivative is2-ethyl-5-methyl-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-one.
 28. Acardiotonic agent according to claim 23 wherein the 1,4-thiazinederivative is5-methyl-6-(3-chloro-4-pyridinyl)-2H-1,4-thiazin-3(4H)-one.
 29. Acardiotonic agent according to claim 23 wherein the 1,4-thiazinederivative is5-methyl-6-(3-formyl-4-pyridinyl)-2H-1,4-thiazin-3(4H)-one.
 30. Acardiotonic agent according to claim 23 wherein the 1,4-thiazinederivative is 5-methyl-6-(3-cyano-4-pyridinyl)-2H-1,4-thiazin-3(4H)-one.31. A cardiotonic agent according to claim 23 wherein the 1,4-thiazinederivative is5-methyl-2-methylamino-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-one.
 32. Acardiotonic agent according to claim 23 wherein the 1,4-thiazinederivative is2-hydroxyphenyl-5-methyl-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-one.
 33. Acardiotonic agent according to claim 23 wherein the 1,4-thiazinederivative is5-methyl-2-morpholino-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-one.